The long term goal of this project is to investigate the functions of nicotinic receptor subpopulations in brain, focusing on potential cytoprotective and memory-enhancing actions of alpha7 receptors for the treatment of Alzheimer's disease. Several hypotheses will be tested: 1) alpha7 receptors protect against apoptotic and necrotic neurotoxic insults by sequentially increasing intracellular calcium concentrations, increasing protein kinase C (pkc) translocation, and elevating bcl-2 levels; 2) accumulation of intracellular calcium ions by the alpha7 selective agonist DMXB is mediated through voltage sensitive calcium channels; 3) mixed agonist/antagonist activity at alpha7 receptors interferes with neuroprotection by attenuating receptor-mediated calcium accumulation; 4) DMXB protects axotomized septal cholinergic neurons selectively by a mechanism that involves activation of septal alpha7 receptors; and 5) alpha7 receptor activation is sufficient to improve memory-related behavior in aged animals. These studies use a combination of approaches, including: enzyme-assays, immunoblotting, histochemistry, patch clamp electrophysiology, and morphological analyses. A variety of assays (e.g., calcium-accumulation, PKC activity, bcl-2 immunohistochemistry) will be conducted in the Chemistry Core associated with this grant.